"Estrogen deprivation syndrome" is a term used to describe various pathological conditions which frequently affect women who have insufficient levels of the hormone estrogen. The most common cause of estrogen deprivation in women is the natural cessation of menses with age, i.e., menopause. Additionally, non-natural circumstances including surgical ovariectomy, chemotherapy causing the cessation of hormone production or pharmacologic action, and the like, may induce estrogen deprivation. Although numerous pathologies are contemplated by the use of this term, two major effects of estrogen deprivation syndrome are the source of the greatest long-term medical concern: osteoporosis and cardiovascular effects, especially hyperlipidemia.
Osteoporosis describes a group of diseases which arise from diverse etiologies, but are all characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass is the failure of the skeleton to provide adequate structural support for the body i.e. bone fracture. One of the most common types of osteoporosis is that associated with menopause. Most women lose from about 20% to about 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after the cessation of menses. This rapid loss is generally associated with an overall increase of the bone resorption and bone formation cycle where the resorptive cycle is more dominant. The obvious result is a net loss of bone mass. Osteoporosis is a common and serious disease among post-menopausal women.
There are an estimated 25 million women in the United States, alone, who are afflicted with this disease. The results of osteoporosis are personally harmful and also account for a large economic loss due its chronicity and the need for extensive and long term support (hospitalization and nursing home care) from the disease sequelae. This is especially true in more elderly patients. Additionally, although osteoporosis is not generally thought of as a life threatening condition, a 20% to 30% mortality rate is attributed to hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with post- menopausal osteoporosis.
Throughout pre-menopausal time, most women have less incidence of cardiovascular disease than age-matched men. Following menopause, however, the rate of cardiovascular disease in women slowly increases to match the rate seen in men. This loss of protection has been linked to the loss of estrogen and, in particular, to the loss of estrogen's ability to regulate the levels of serum lipids. The nature of estrogen's ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen can upregulate the low density lipid (LDL) receptors in the liver to remove excess cholesterol. Additionally, estrogen appears to have some effect on the biosynthesis of cholesterol, and other beneficial effects on cardiovascular health.
Although estrogen replacement therapy is often prescribed for the estrogen deprivation syndrome, it suffers from poor patient compliance as many women object to some of the side-effects and the inconvenience of the pharmaceutical forms of the medication. For example, 17-.beta.-estradiol is often administered via a transdermal patch, due to its poor oral absorption. As a result, a majority of women cease taking estrogen within the first year of beginning estrogen replacement therapy.
Compounds of formula I: ##STR2## where: R and R.sup.1 are independently hydrogen, hydroxy, C.sub.1 -C.sub.6 alkoxy, OCH.sub.2 Ar, OCO(C.sub.1 -C.sub.6 alkyl), OCOAr; and
Ar is phenyl or substituted phenyl; PA1 Ar is phenyl or substituted phenyl; or a solvate thereof. PA1 2-phenylbenzo[b]thiophene; PA1 2-(4-hydroxyphenyl)benzo[b]thiophene; PA1 2-(4-methoxyphenyl)benzo[b]thiophene; PA1 2-(4-acetoxyphenyl)benzo[b]thiophene; PA1 2-(4-benzoyloxyphenyl)benzo[b]thiophene; PA1 2-(4-isopropoxyphenyl)benzo[b]thiophene; PA1 2-phenyl-6-hydroxybenzo[b]thiophene; PA1 2-phenyl-6-methoxybenzo[b]thiophene; PA1 2-phenyl-6-isopropoxybenzo[b]thiophene; PA1 2-phenyl-6-acetoxybenzo[b]thiophene; PA1 2-phenyl-6-(4-methylbenzoyl)oxybenzo[b]thiophene; PA1 2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thiophene; PA1 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene; PA1 2-(4-methoxyphenyl)-6-hydroxybenzo[b]thiophene; PA1 2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene; PA1 2-(4-isopropoxyphenyl)-6-methoxybenzo[b]thiophene; PA1 2-(4-isopropoxyphenyl)-6-hydroxybenzo[b]thiophene; PA1 2-(4-methoxyphenyl)-6-isopropoxybenzo[b]thiophene; PA1 2-(4-hydroxyphenyl)-6-isopropoxybenzo[b]thiophene; PA1 2-(4-acetoxyphenyl)-6-acetoxybenzo[b]thiophene; PA1 2-(4-methoxyphenyl)-6-acetoxybenzo[b]thiophene; PA1 2-(4-acetoxyphenyl)-6-methoxybenzo[b]thiophene; PA1 2-(4-acetoxyphenyl)-6-hydroxybenzo[b]thiophene; PA1 2-(4-hydroxyphenyl)-6-acetoxybenzo[b]thiophene; PA1 2-(4-benzoyloxyphenyl)-6-hydroxybenzo[b]thiophene; PA1 2-(4-benzoyloxyphenyl)-6-enzoyloxybenzo[b]thiophene; PA1 2-(4-cyclopentoxyphenyl)-6-hydroxybenzo[b]thiophene; PA1 2-(4-hydroxyphenyl)-6-cyclopentoxybenzo[b]thiophene; PA1 2-(4-cyclopentoxyphenyl)-6-cyclopentoxybenzo[b]thiophene; PA1 2-(4-butoyloxyphenyl)-6-hydroxybenzo[b]thiophene; PA1 2-(4-cyclopentoxyphenyl)-6-acetoxybenzo[b]thiophene; and the like. PA1 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)etho xy]phenyl]methanone hydrochloride; PA1 2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)etho xy]phenyl]methanone hydrochloride; PA1 2-(4-methoxyphenyl)-6-hydroxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)etho xy]phenyl]methanone hydrochloride; PA1 2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)etho xy]phenyl]methanone hydrochloride; PA1 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)etho xy]phenyl]methanone N-oxide; PA1 2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)etho xy]phenyl]methanone N-oxide; PA1 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-pyrolidinyl)etho xy]phenyl]methanone hydrochloride; PA1 2-(4-methoxyphenyl)-6-hydroxybenzo[b]thiophene and [2-(4-methoxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)etho xy]phenyl]methanone hydrochloride; PA1 2-(4-acetoxyphenyl)-6-acetoxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)etho xy]phenyl]methanone hydrochloride; PA1 2-(4-cyclopentoxyphenyl)-6-methoxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(l-piperidinyl)etho xy]phenyl]methanone hydrochloride; PA1 2-(4-methoxyphenyl)-6-hydroxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)etho xy]phenyl]methanone N-oxide; PA1 2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene and [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)etho xy]phenyl]methanone N-oxide; and the like.
are known as chemical intermediates to oral pharmaceutical agents, e.g. raloxifene hydrochloride.
The present invention concerns the discovery of utilities newly attributed to compounds of formula I, namely, that they are agents useful in inhibiting estrogen deprivation syndrome.